Mitochondria are central to cellular metabolism, which provides both energy to sustain biological activities and metabolic intermediates for biosynthesis. Glucose as well as lipids such as triglyceride are the most important fuels of cells. Glucose first metabolizes to pyruvate through glycolysis. In turn, pyruvate enters mitochondria, where it converts to acetyl-CoA. Similarly, triglyceride is first hydrolyzed to glycerol and fatty acid, which enter mitochondria, where they are oxidized to acetyl-CoA. In mitochondrial matrix, acetyl-CoA from glucose metabolism as well as lipid metabolism is then oxidized through TCA cycle. The energy released from the oxidation reactions is stored in the form of high energy electrons in the molecules of NADH and FADH2. Electrons from NADH and FADH2 are in turn fed into the mitochondrial electron transporter chain, which are localized on the inner membrane of mitochondria. As the electrons travel through the electron transporter chain and reach the electron receptor, oxygen molecule, energy is released and used for pumping protons from mitochondrial matrix across the mitochondrial inner membrane, establishing a proton gradient across the membrane. Finally, protons travel across the mitochondrial inner membrane through the FoF1-ATP synthase and drive the synthesis of ATP, the energy molecule that can be directly used by the various cellular machineries. Under normal conditions, mitochondrial oxidation provides more than 90% of cellular ATP. In addition, mitochondrial oxidation provides and regulates the availability of metabolic intermediates required for biosynthesis of macromolecules such as RNA, DNA, lipids.
Generally, mitochondrial oxidation of acetyl-CoA and ATP synthesis are coupled in response to cellular energy needs. However, mitochondrial oxidation can be decoupled from ATP synthesis by mitochondrial uncouplers. Mitochondrial uncouplers facilitate the inward translocation of protons across mitochondrial inner membrane (not through the FoF1-ATP synthase), thus dissipate or reduce the proton gradient without generating ATP. Mitochondrial uncoupling could be mediated by protein mitochondrial uncouplers such as UCP1 protein, or chemical uncouplers such as DNP (dinitrophenol). As a result, mitochondrial uncouplers usually lead to the following effects: (1). reduction of mitochondrial energy efficiency, (2). increase of lipid and glucose oxidation, (3). activation of AMPK enzyme, (4). alteration of availability of metabolic intermediates for biomass biosynthesis required for cell proliferation.
Although chemical uncouplers of mitochondria have been reported in literature, there remains a need for the discovery of new types of chemical mitochondrial uncouplers with a combination of favorable pharmacokinetic and pharmacodynamic properties.